In a recent publication, J. Org. Chem. 1985, 50, 5480-5484, B. Rajashekhar et al. describe a six step synthesis of .gamma.-amino-.beta.-hydroxybutyric acid using malic acid as the starting material. The authors characterize their method as simpler and more efficient in a 25-30% yield than that of Jung et al. (1980) which involves a nine step synthesis in which ascorbic acid is the starting material and yield is about 10%.
The method of the invention is carried out in a series of steps as set forth herein; namely:
(a) a (2S,4R)-4-hydroxyproline ester hydrochloride of the formula: ##STR1## in which R signifies a methyl or ethyl group and the symbol "x" indicates the hydrochloride salt, is converted by being treated in a water-free medium with an alkali metal methoxide or alkali metal ethoxide at first, then t-butyl hypochlorite and finally triethyl amine into the (R)-4-hydroxy-1-pyrroline-2-carboxylic acid ester of the formula: ##STR2## in which R again has the same meaning already indicated above,
(b) the latter compound of formula II is dissolved without further purification in an alkali metal hydroxide solution, the solution is treated with hydrogen peroxide, the resulting reaction mixture is acidified by slowly adding a mineral acid and subsequently desalinated and the thereby formed (R)-4-hydroxy-2-pyrrolidone of the formula: ##STR3## is isolated by concentration using evaporation and thereafter
(c) the latter (III) is hydrolyzed with a mineral acid to form (R)-4-amino-3-hydroxybutyric acid of the formula: ##STR4##
Since the 4-hydroxyproline derivative of formula (I) functioning as the initial starting material can be prepared for its part in a relatively simple manner from the naturally occurring L-4-hydroxyproline, the method of the present invention provides a relatively simple and economical pathway from the latter to (R)-4-amino-3-hydroxybutyric acid.
The (R)-4-amino-3-hydroxybutyric acid itself, obtainable in a high yield in accordance with the method of the present invention, as well as the trimethyl betaine L-carnitine which is readily obtainable therefrom are compounds that have pharmacologically significant applications. It is a known compound having neuromodulator properties for the central nervous system.
In the practical implementation of the method of the present invention, the (2S,4R)-4-hydroxyproline ester must first be released from the (2S,4R)-4-hydroxyproline ester hydrochloride of formula (I) by means of a treatment with an alkali metal methoxide or alkali metal ethoxide. The methoxides and ethoxides of sodium and potassium, which are added advantageously as solution in the corresponding alcohol, are especially well suited for this purpose. The use of a solution of sodium methoxide in absolute methanol is preferred. The alkali metal methoxide or alkali metal ethoxide is preferably used in a 1 to 1.05-fold, especially in a 1 to 1.01-fold molar amount of the (2S,4R)-4-hydroxyproline ester hydrochloride present. The temperature is advantageously between 10.degree. C. and 30.degree. C., preferably between 15.degree. C. and 25.degree. C.
The subsequent treatment of the released (2S,4R)-4-hydroxyproline ester with t-butyl hypochlorite should advantageously be performed in a more non-polar solvent, and therefore, it is advantageous if the alcohol is removed as completely as possible under mild conditions and the residue is taken up in absolute tetrahydrofurane or 1,2-dimethoxyethane or in a mixture of one of these ethers and absolute diethyl ether. The t-butyl hypochlorite is preferably used in a 1 to 1.05-fold, especially in a 1 to 1.02-fold molar amount of the (2S,4R)-4-hydroxyproline ester hydrochloride originally used. The temperature should be maintained advantageously between -40.degree. C. and -20.degree. C.
When the reaction with the t-butyl hypochlorite, which serves for the N-chlorination of the (2S,4R)-4-hydroxyproline ester, has ended, the N-chlorine derivative is subsequently treated without the need for intermediary isolation in the same solvent (mixture) with triethyl amine. The double bond between the nitrogen atom and the carbon atom in the 2-position is formed thereby under dehydrochlorination and the (R)-4-hydroxy-1-pyrroline-2-carboxylic acid ester of formula (II) is created. The triethyl amine is advantageously used in that reaction step in a 1 to 1.05-fold, preferably in a 1 to 1.03-fold molar amount (per mole) of the (2S,4R)-4-hydroxyproline ester hydrochloride originally used. The temperature is advantageously held between -20.degree. C. and +10.degree. C.
It is advantageous if the reaction mixture is allowed to stand for a fairly long time, e.g. overnight (about 16 hours), at a temperature between 0.degree. and +10.degree. C. after the addition of the triethyl amine. Thereafter, the deposited salts are separated and washed with fresh solvent (mixture). The combined filtrates are concentrated by evaporation in a mild manner under reduced pressure.
The (R)-4-hydroxy-1-pyrroline-2-carboxylic acid ester remaining as an oil is subsequently taken up without further purification in an aqueous alkali metal hydroxide solution, preferably sodium hydroxide solution, and reacted with an aqueous solution of hydrogen peroxide. Then, a mineral acid, preferably sulfuric acid or hydrochloric acid, is slowly added. The reaction mixture is allowed to stand for a while at a moderately elevated temperature before the excess hydrogen peroxide is destroyed, e.g. by means of adding an aqueous sodium sulfite solution. In this (b) reaction stage, the alkali metal hydroxide and the hydrogen peroxide are advantageously used in a 1 to 1.05-fold, preferably in a 1 to 1.03-fold molar amount of the (2S,4R)-4-hydroxyproline ester hydrochloride originally used and the mineral acid in an amount which is at least equivalent to the alkali metal hydroxide added. The temperature in this (b) reaction stage is advantageously between 20.degree. C. and 50.degree. C., preferably between 20.degree. C. and 40.degree. C.
The acidified reaction mixture is then desalinated, optionally after some concentration by evaporation under reduced pressure, by being treated with a strongly acidic ion exchanger in the H.sup.+ form and with a strongly basic ion exchanger in the HO.sup.- form and the desalinated solution is concentrated by evaporation under reduced pressure until dry. The residue is advantageously treated several times with absolute ethanol and again concentrated by evaporation in order to remove residual water and is finally treated with absolute diethyl ether. The resulting crystals of (R)-4-hydroxy-2-pyrrolidone of formula (III) obtained can be sublimated for further purification in a high vacuum.
Finally, the (R)-4-hydroxy-2-pyrrolidone of formula (III) is hydrolyzed in excess mineral acid, preferably sulfuric acid and especially hydrochloric acid. The mineral acid is advantageously added in a 5 to 10-fold, preferably a 5 to 6-fold molar amount (per mole) of the (R)-4-hydroxy-2-pyrrolidone present and in a concentration between 4N and 6N. The hydrolysis temperature can be e.g. between 90.degree. C. and the reflux temperature of the reaction mixture. The hydrolysis is preferably performed by heating under reflux.
After the hydrolysis has been completed, the reaction mixture, for example, can be worked up in such a manner that it is treated with a strongly acidic ion exchanger in the H.sup.+ form and the (R)-4-amino-3-hydroxybutyric acid is eluted with diluted, aqueous ammonia solution. The eluate is then concentrated by evaporation under reduced pressure until dry. The remaining (R)-4-amino-3-hydroxybutyric acid of formula (IV) can be recrystallized for further purification, optionally with the addition of activated carbon, from a water/ethanol mixture.